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1.  Locomotion control of hybrid cockroach robots 
Journal of the Royal Society Interface  2015;12(105):20141363.
Natural systems retain significant advantages over engineered systems in many aspects, including size and versatility. In this research, we develop a hybrid robotic system using American (Periplaneta americana) and discoid (Blaberus discoidalis) cockroaches that uses the natural locomotion and robustness of the insect. A tethered control system was firstly characterized using American cockroaches, wherein implanted electrodes were used to apply an electrical stimulus to the prothoracic ganglia. Using this approach, larger discoid cockroaches were engineered into a remotely controlled hybrid robotic system. Locomotion control was achieved through electrical stimulation of the prothoracic ganglia, via a remotely operated backpack system and implanted electrodes. The backpack consisted of a microcontroller with integrated transceiver protocol, and a rechargeable battery. The hybrid discoid roach was able to walk, and turn in response to an electrical stimulus to its nervous system with high repeatability of 60%.
PMCID: PMC4387526  PMID: 25740855
biotechnology; hybrid robotics; insect control
2.  Motivational Interviewing and Dietary Counseling for Obesity in Primary Care: An RCT 
Pediatrics  2015;135(4):649-657.
Few studies have tested the impact of motivational interviewing (MI) delivered by primary care providers on pediatric obesity. This study tested the efficacy of MI delivered by providers and registered dietitians (RDs) to parents of overweight children aged 2 through 8.
Forty-two practices from the Pediatric Research in Office Settings Network of the American Academy of Pediatrics were randomly assigned to 1 of 3 groups. Group 1 (usual care) measured BMI percentile at baseline and 1- and 2-year follow-up. Group 2 (provider only) delivered 4 MI counseling sessions to parents of the index child over 2 years. Group 3 (provider + RD) delivered 4 provider MI sessions plus 6 MI sessions from a RD. The primary outcome was child BMI percentile at 2-year follow up.
At 2-year follow-up, the adjusted BMI percentile was 90.3, 88.1, and 87.1 for groups 1, 2, and 3, respectively. The group 3 mean was significantly (P = .02) lower than group 1. Mean changes from baseline in BMI percentile were 1.8, 3.8, and 4.9 across groups 1, 2, and 3.
MI delivered by providers and RDs (group 3) resulted in statistically significant reductions in BMI percentile. Research is needed to determine the clinical significance and persistence of the BMI effects observed. How the intervention can be brought to scale (in particular, how to train physicians to use MI effectively and how best to train RDs and integrate them into primary care settings) also merits future research.
PMCID: PMC4379459  PMID: 25825539
3.  Targeted blockade of JAK/STAT3 signaling inhibits ovarian carcinoma growth 
Molecular cancer therapeutics  2015;14(4):1035-1047.
Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy.
PMCID: PMC4394029  PMID: 25646015
JAK; STAT3; ovarian cancer; AZD1480
4.  Voltage Controlled Magnetic Skyrmion Motion for Racetrack Memory 
Scientific Reports  2016;6:23164.
Magnetic skyrmion, vortex-like swirling topologically stable spin configurations, is appealing as information carrier for future nanoelectronics, owing to the stability, small size and extremely low driving current density. One of the most promising applications of skyrmion is to build racetrack memory (RM). Compared to domain wall-based RM (DW-RM), skyrmion-based RM (Sky-RM) possesses quite a few benefits in terms of energy, density and speed etc. Until now, the fundamental behaviors, including nucleation/annihilation, motion and detection of skyrmion have been intensively investigated. However, one indispensable function, i.e., pinning/depinning of skyrmion still remains an open question and has to be addressed before applying skyrmion for RM. Furthermore, Current research mainly focuses on physical investigations, whereas the electrical design and evaluation are still lacking. In this work, we aim to promote the development of Sky-RM from fundamental physics to realistic electronics. First, we investigate the pinning/depinning characteristics of skyrmion in a nanotrack with the voltage-controlled magnetic anisotropy (VCMA) effect. Then, we propose a compact model and design framework of Sky-RM for electrical evaluation. This work completes the elementary memory functionality of Sky-RM and fills the technical gap between the physicists and electronic engineers, making a significant step forward for the development of Sky-RM.
PMCID: PMC4791601  PMID: 26975697
5.  Data Harmonization in Aging Research: Not So Fast 
Experimental aging research  2015;41(5):475-495.
Background/Study Context
Harmonizing measures in order to conduct pooled data analyses has become a scientific priority in aging research. Retrospective harmonization where different studies lack common measures of comparable constructs presents a major challenge. This study compared different approaches to harmonization with a crosswalk sample who completed multiple versions of the measures to be harmonized.
Through online recruitment, 1061 participants aged 30 to 98 answered two different depression scales, and 1065 participants answered multiple measures of subjective health. Rational and configural methods of harmonization were applied, using the crosswalk sample to determine their success; and empirical item response theory (IRT) methods were applied in order empirically to compare items from different measures as answered by the same person.
For depression, IRT worked well to provide a conversion table between different measures. The rational method of extracting semantically matched items from each of the two scales proved an acceptable alternative to IRT. For subjective health, only configural harmonization was supported. The subjective health items used in most studies form a single robust factor.
Caution is required in aging research when pooling data across studies using different measures of the same construct. Of special concern are response scales that vary widely in the number of response options, especially if the anchors are asymmetrical. A crosswalk sample that has completed items from each of the measures being harmonized allows the investigator to use empirical approaches to identify flawed assumptions in rational or configural approaches to harmonizing.
PMCID: PMC4772674  PMID: 26524232
Crosswalk table; data harmonization; data sharing; integrative data analysis; item response theory; pooled data analysis; Rasch analysis; depression; self-rated health
6.  Chlorogenic acid from honeysuckle improves hepatic lipid dysregulation and modulates hepatic fatty acid composition in rats with chronic endotoxin infusion 
Chlorogenic acid as a natural hydroxycinnamic acid has protective effect for liver. Endotoxin induced metabolic disorder, such as lipid dysregulation and hyperlipidemia. In this study, we investigated the effect of chlorogenic acid in rats with chronic endotoxin infusion. The Sprague-Dawley rats with lipid metabolic disorder (LD group) were intraperitoneally injected endotoxin. And the rats of chlorogenic acid-LD group were daily received chlorogenic acid by intragastric administration. In chlorogenic acid-LD group, the area of visceral adipocyte was decreased and liver injury was ameliorated, as compared to LD group. In chlorogenic acid-LD group, serum triglycerides, free fatty acids, hepatic triglycerides and cholesterol were decreased, the proportion of C20:1, C24:1 and C18:3n-6, Δ9-18 and Δ6-desaturase activity index in the liver were decreased, and the proportion of C18:3n-3 acid was increased, compared to the LD group. Moreover, levels of phosphorylated AMP-activated protein kinase, carnitine palmitoyltransferase-I, and fatty acid β-oxidation were increased in chlorogenic acid-LD group compared to LD rats, whereas levels of fatty acid synthase and acetyl-CoA carboxylase were decreased. These findings demonstrate that chlorogenic acid effectively improves hepatic lipid dysregulation in rats by regulating fatty acid metabolism enzymes, stimulating AMP-activated protein kinase activation, and modulating levels of hepatic fatty acids.
PMCID: PMC4788397  PMID: 27013782
chlorogenic acid; lipid metabolism; fatty acids; AMP-activated protein kinase
7.  A novel M2e-multiple antigenic peptide providing heterologous protection in mice 
Journal of Veterinary Science  2016;17(1):71-78.
Swine influenza viruses (SwIVs) cause considerable morbidity and mortality in domestic pigs, resulting in a significant economic burden. Moreover, pigs have been considered to be a possible mixing vessel in which novel strains loom. Here, we developed and evaluated a novel M2e-multiple antigenic peptide (M2e-MAP) as a supplemental antigen for inactivated H3N2 vaccine to provide cross-protection against two main subtypes of SwIVs, H1N1 and H3N2. The novel tetra-branched MAP was constructed by fusing four copies of M2e to one copy of foreign T helper cell epitopes. A high-yield reassortant H3N2 virus was generated by plasmid based reverse genetics. The efficacy of the novel H3N2 inactivated vaccines with or without M2e-MAP supplementation was evaluated in a mouse model. M2e-MAP conjugated vaccine induced strong antibody responses in mice. Complete protection against the heterologous swine H1N1 virus was observed in mice vaccinated with M2e-MAP combined vaccine. Moreover, this novel peptide confers protection against lethal challenge of A/Puerto Rico/8/34 (H1N1). Taken together, our results suggest the combined immunization of reassortant inactivated H3N2 vaccine and the novel M2e-MAP provided cross-protection against swine and human viruses and may serve as a promising approach for influenza vaccine development.
PMCID: PMC4808646  PMID: 27051342
H3N2; M2e-multiple antigenic peptide; high-yield; inactivated vaccine; swine influenza virus
8.  Targeting Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer by Inducing Epidermal Growth Factor Receptor Degradation via Methionine 790 Oxidation 
Antioxidants & Redox Signaling  2016;24(5):263-279.
Aims: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation, but TKI resistance is common. Almost half of the acquired resistance patients are due to additional T790M mutation on EGFR (EGFRT790M), thus overcoming TKI resistance is important. In this study, we aim to investigate the role of reactive oxygen species (ROS) in TKI resistance as well as the molecular and biological effects of EGFRT790M after redox manipulation. Results: The basal ROS levels in EGFRT790M-containing TKI-resistant NSCLC cell lines were substantially high. Sixty-three human lung tumors showed higher NADPH oxidase isoform 2 (NOX2) expression than normal lung tissues, which may contribute to high basal ROS in cancer and poor survival. Interestingly, only NOX3 was upregulated by sanguinarine, a pharmacological agent to elevate ROS, and resulted in EGFR overoxidation, degradation, and apoptosis. By contrast, such responses were lacking in EGFRWT cells. Selective EGFRT790M degradation was manipulated by redox imbalance between NOX3 and methionine reductase A (MsrA). Furthermore, the in vivo tumor suppression effect of sanguinarine, NOX3 upregulation, and EGFR degradation were confirmed. Innovation: We have found a new treatment strategy to overcome TKI resistance by selectively inducing EGFRT790M degradation via specific stimulation of methionine 790 (M790) oxidation. It can be achieved via manipulating redox imbalance between NOX3 and MsrA. Conclusion: Targeting EGFR by elevating ROS and redox imbalance is a potential new strategy to develop a new EGFR inhibitor for TKI-resistant patients with a wide therapeutic window between EGFRT790M and EGFRWT. Antioxid. Redox Signal. 24, 263–279.
PMCID: PMC4753639  PMID: 26528827
9.  Molecular characterization of the Haemonchus contortus phosphoinositide-dependent protein kinase-1 gene (Hc-pdk-1) 
Parasites & Vectors  2016;9:65.
Phosphoinositide-dependent protein kinase-1 (PDK-1), which functions downstream of phosphoinositide 3-kinase (AGE-1) and activates protein kinases of the AGC family, plays critical roles in regulating biology processes, such as metabolism, growth, development and survival. In the free-living nematode Caenorhabditis elegans, PDK-1 is a key component of the insulin-like signalling pathway, regulating the entry into and exit from dauer (arrested development). Although it is proposed that similar molecular mechanisms control the transition from the free-living to the parasitic stages of nematodes, nothing is known about PDK-1 in Haemonchus contortus, a socioeconomically important gastric nematode of ruminants.
Here, we isolated and characterized the pdk-1 gene (Hc-pdk-1) and its inferred product (Hc-PDK-1) from H. contortus. Using in vitro and in vivo methods, we then studied the transcriptional profiles of Hc-pdk-1 and anatomical gene expression patterns of Hc-PDK-1 in different developmental stages of C. elegans.
In silico analysis of Hc-PDK-1 displayed conserved functional domains, such as protein kinase and pleckstrin homology (PH) domains and two predicted phosphorylation sites (Thr226/Tyr229), which are crucial for the phosphorylation of downstream signalling. The Hc-pdk-1 gene is transcribed in all of the main developmental stages of H. contortus, with its highest transcription in the infective third-stage larvae (iL3) compared with other stages. Transgene constructs, in which respective promoters were fused to the coding sequence for green fluorescent protein (GFP), were used to transform C. elegans, and to localize and compare the expression of Hc-pdk-1 and Ce-pdk-1. The expression of GFP under the control of the Hc-pdk-1 promoter was localized to the intestine, and head and tail neurons, contrasting somewhat the profile for the C. elegans ortholog, which is expressed in pharynx, intestine and head and tail neurons.
This is the first characterization of pdk-1/PDK-1 from a trichostrongyloid nematode. Taken together, the findings from this study provide a first glimpse of the involvement of Hc-pdk-1 in the insulin-like signalling pathway in H. contortus.
Electronic supplementary material
The online version of this article (doi:10.1186/s13071-016-1351-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4741024  PMID: 26842781
Haemonchus contortus; Transgenesis; Development; pdk-1 gene
10.  Individual differences in gene expression of vasopressin, D2 receptor, POMC and orexin: vulnerability to relapse to heroin-seeking in rats 
Physiology & behavior  2014;139:127-135.
Individual vulnerability to stress-induced relapse during abstinence from chronic heroin exposure is a key feature of opiate addiction, with limited studies on this topic. Arginine vasopressin (AVP) and its V1b receptor, components of the brain stress responsive systems, play a role in heroin-seeking behavior triggered by foot shock (FS) stress in rats. In this study, we tested whether individual differences in the FS-induced heroin-seeking were associated with alterations of AVP and V1b, as well as other stress responsive systems, including pro-opiomelanocortin (POMC), orexin, plasma ACTH and corticosterone, as well as dopamine D2 receptor (D2) and plasma prolactin. Sprague-Dawley rats were subjected to 3-hour intravenous heroin self-administration (SA) and then tested in extinction, FS-induced and heroin priming-induced reinstatements. The rats that self-administered heroin were divided to high and low reinstatement responders induced by FS (H-RI; L-RI). Over SA sessions, both the H-RI and L-RI displayed similar active lever responding, heroin infusion and total heroin intake. Compared to the L-RI, however, the H-RI showed greater active lever responses during stress-induced reinstatement, with higher AVP mRNA levels in medial/basolateral amygdala and lower D2 mRNA levels in caudate putamen. However, heroin priming resulted in similar reinstatement in both groups and produced similarly low POMC and high orexin mRNA levels in hypothalamus. Our results indicate that: 1) enhanced amygdalar AVP and reduced striatal D2 expression may be related to individual vulnerability to stress-induced reinstatement of heroin- seeking; and 2) heroin abstinence-associated alterations of hypothalamic orexin and POMC expression may be involved in drug priming-induced heroin-seeking.
PMCID: PMC4275356  PMID: 25446223
arginine vasopressin; POMC; orexin; D2; stress; heroin-seeking behavior
11.  Bio-inspired hard-to-soft interface for implant integration to bone 
Accomplishing full, functional integration at the host-to-biomaterial interface has been a critical roadblock in engineering implants with performance similar to biological materials. Molecular recognition-based self-assembly, coupled with biochemical signaling, may lead to controllable and predictable cellular differentiation at the implant interface. Here, we engineer a bio-inspired interface built upon a chimeric peptide. Binding to the biomaterial interface is achieved using a molecular recognition domain specific for the titanium/titanium alloy implant surface and a biochemical signal guiding stem cells to differentiate by activating the Wnt signaling pathway for bone formation. During a critical period of host cell growth and determination, the bioactive implant interface signals mouse, as well as human, stem cells to differentiate along osteogenic lineages. The Wnt-induced cells show enhanced mineral deposition in an extracellular matrix of their creation and an enhanced gene expression profile consistent with osteogenesis, thereby providing a bone-to-implant interface that promotes bone regeneration.
PMCID: PMC4330108  PMID: 25461292
Biomaterial Interface; Chimeric Peptide; Wnt signaling; Osteogenesis; Bone Regeneration
12.  Identification of TRIML2, a Novel p53 Target, that Enhances p53-SUMOylation and Regulates the Transactivation of Pro-apoptotic Genes 
Molecular cancer research : MCR  2014;13(2):250-262.
The tumor suppressor protein p53, encoded by TP53, inhibits tumorigenesis by inducing cell cycle arrest, senescence and apoptosis. Several genetic polymorphisms exist in TP53, including a proline to arginine variant at amino acid 72 (P72 and R72, respectively); this polymorphism alters p53 function. In general, the P72 variant shows increased ability to induce cell cycle arrest, while the R72 variant possesses increased ability to induce apoptosis, relative to P72. At present, the underlying mechanisms for these functional differences are not fully understood. Toward elucidating the molecular basis for these differences a gene expression microarray analysis was conducted on normal human fibroblast cells that are homozygous for P72 and R72 variants, along with subclones of these lines that express a p53 short hairpin (shp53). Approximately three dozen genes were identified whose transactivation is affected by the codon 72 polymorphism. One of these is the tripartite motif family-like 2 (TRIML2) gene, which is preferentially induced by the R72 variant. Importantly, the accumulated data indicate that TRIML2 interacts with p53, and facilitates the modification of p53 with SUMO2. TRIML2 also enhances the ability of p53 to transactivate a subset of pro-apoptotic target genes associated with prolonged oxidative stress, including PIDD, PIG3 (TP53I3) and PIG6 (PRODH). These data indicate that TRIML2 is part of a feed-forward loop that activates p53 in cells expressing the R72 variant, particularly after prolonged stress.
PMCID: PMC4336799  PMID: 25256710
p53; TRIML2; apoptosis; DNA damage; Pidd; Pig3; Pig6
13.  Improved survival of porcine acute liver failure by a bioartificial liver device implanted with induced human functional hepatocytes 
Cell Research  2016;26(2):206-216.
Acute liver failure (ALF) is a life-threatening illness. The extracorporeal cell-based bioartificial liver (BAL) system could bridge liver transplantation and facilitate liver regeneration for ALF patients by providing metabolic detoxification and synthetic functions. Previous BAL systems, based on hepatoma cells and non-human hepatocytes, achieved limited clinical advances, largely due to poor hepatic functions, cumbersome preparation or safety concerns of these cells. We previously generated human functional hepatocytes by lineage conversion (hiHeps). Here, by improving functional maturity of hiHeps and producing hiHeps at clinical scales (3 billion cells), we developed a hiHep-based BAL system (hiHep-BAL). In a porcine ALF model, hiHep-BAL treatment restored liver functions, corrected blood levels of ammonia and bilirubin, and prolonged survival. Importantly, human albumin and α-1-antitrypsin were detectable in hiHep-BAL-treated ALF pigs. Moreover, hiHep-BAL treatment led to attenuated liver damage, resolved inflammation and enhanced liver regeneration. Our findings indicate a promising clinical application of the hiHep-BAL system.
PMCID: PMC4746613  PMID: 26768767
acute liver failure; functional hepatocytes; bioartificial liver
14.  Molecular Characteristic, Protein Distribution and Potential Regulation of HSP90AA1 in the Anadromous Fish Coilia nasus 
Genes  2016;7(2):8.
Heat shock proteins play essential roles in basic cellular events. Spawning migration is a complex process, with significant structural and biochemical changes taking place in the adult gonad. To date, the molecular mechanisms underlying migration reproductive biology remain undetermined. In this regard, a full length HSP90AA1 comprising 2608 nucleotides from the anadromous fish Coilia nasus was characterized, encoding 742 amino acid (aa) residues with potential phosphorylation sites. HSP90AA1 mRNA transcripts were detected in all organs, especially in the gonad. Furthermore, the greatest transcript levels were found during the developmental phase, while the lowest levels were found during the resting phase. In addition, the strongest immunolabeling positive signal was found in the primary spermatocyte and oocyte, with lower positive staining in secondary germ cells, and a weak or absent level in the mature sperm and oocyte. Interestingly, HSP90AA1 was mainly located in the cytoplasm of germ cells. These results are important for understanding the molecular mechanism of anadromous migration reproductive biology. In combination with data from other fish species, the result of this present study may facilitate further investigations on the spawning migration mechanism.
PMCID: PMC4773752  PMID: 26828521
Coilia nasus; HSP90AA1 expression; anadromous fish; migration mechanism
15.  Interactions between 2-Cys peroxiredoxins and ascorbate in autophagosome formation during the heat stress response in Solanum lycopersicum  
Journal of Experimental Botany  2016;67(6):1919-1933.
2-Cys peroxiredoxins fulfil a pivotal role in heat stress tolerance in Solanum lycopersicum via interactions with ascorbate-dependent pathways and autophagy.
2-Cys peroxiredoxins (2-CPs) function in the removal of hydrogen peroxide and lipid peroxides but their precise roles in the induction of autophagy have not been characterized. Here we show that heat stress, which is known to induce oxidative stress, leads to the simultaneous accumulation of transcripts encoding 2-CPs and autophagy proteins, as well as autophagosomes, in tomato (Solanum lycopersicum) plants. Virus-induced gene silencing of the tomato peroxiredoxin genes 2-CP1, 2-CP2, and 2-CP1/2 resulted in an increased sensitivity of tomato plants to heat stress. Silencing 2-CP2 or 2-CP1/2 increased the levels of transcripts associated with ascorbate biosynthesis but had no effect on the glutathione pool in the absence of stress. However, the heat-induced accumulation of transcripts associated with the water-water cycle was compromised by the loss of 2-CP1/2 functions. The transcript levels of autophagy-related genes ATG5 and ATG7 were higher in plants with impaired 2-CP1/2 functions, and the formation of autophagosomes increased, together with an accumulation of oxidized and insoluble proteins. Silencing of ATG5 or ATG7 increased the levels of 2-CP transcripts and protein but decreased heat stress tolerance. These results demonstrate that 2-CPs fulfil a pivotal role in heat stress tolerance in tomato, via interactions with ascorbate-dependent pathways and autophagy.
PMCID: PMC4783371  PMID: 26834179
antioxidant metabolism; autophagy; 2-Cys peroxiredoxin; heat tolerance; oxidized protein; Solanum; lycopersicum; water-water cycle.
16.  Overexpression of a brassinosteroid biosynthetic gene Dwarf enhances photosynthetic capacity through activation of Calvin cycle enzymes in tomato 
BMC Plant Biology  2016;16:33.
Genetic manipulation of brassinosteroid (BR) biosynthesis or signaling is a promising strategy to improve crop yield and quality. However, the relationships between the BR-promoted growth and photosynthesis and the exact mechanism of BR-regulated photosynthetic capacity are not clear. Here, we generated transgenic tomato plants by overexpressing Dwarf, a BR biosynthetic gene that encodes the CYP85A1, and compared the photosynthetic capacity with the BR biosynthetic mutant dim and wild type.
Overexpression of Dwarf promoted net photosynthetic rate (PN), whereas BR deficiency in dim led to a significant inhibition in PN as compared with WT. The activation status of RuBisCO, and the protein content and activity of RuBisCO activase, but not the total content and transcripts of RuBisCO were closely related to the endogenous BR levels in different genotypes. However, endogenous BR positively regulated the expression and activity of fructose-1,6-bisphosphatase. Dwarf overexpression enhanced the activity of dehydroascorbate reductase and glutathione reductase, leading to a reduced redox status, whereas BR deficiency had the contrasting effects. In addition, BR induced a reduction of 2-cystein peroxiredoxin without altering the protein content.
BR plays a role in the regulation of photosynthesis. BR can increase the photosynthetic capacity by inducing a reduced redox status that maintains the activation states of Calvin cycle enzymes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-016-0715-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4730719  PMID: 26822290
Brassinosteroids; 2-cystein peroxiredoxins; Dwarf; Glutathione; Photosynthesis; RuBisCO
17.  Targeting and retention enhancement of quantum dots decorated with amino acids in an invertebrate model organism 
Scientific Reports  2016;6:19802.
The use of quantum dots (QDs) in biological imaging applications and targeted drug delivery is expected to increase. However, the efficiency of QDs in drug targeting needs to be improved. Here, we show that amino acids linked to CdTe QDs significantly increased the targeted transfer efficiency and biological safety in the invertebrate model Bombyx mori. Compared with bare QDs530, the transfer efficiency of Ala- and Gly-conjugated QDs (QDs530-Ala and QDs530-Gly) in circulatory system increased by 2.6 ± 0.3 and 1.5 ± 0.3 times, and increased by 7.8 ± 0.9 and 2.9 ± 0.2 times in target tissue silk glands, respectively, after 24 h of QDs exposure. Meanwhile, the amount of conjugated QDs decreased by (68.4 ± 4.4)% and (46.7 ± 9.1)% in the non-target tissue fat body, and the speed at which they entered non-target circulating blood cells significantly decreased. The resultant QDs530-Ala revealed a better structural integrity in tissues and a longer retention time in hemolymph than that of QDs530 after exposure via the dorsal vessel. On the other hand, QDs530-Ala significantly reduced the toxicity to hemocytes, silk gland, and fat body, and reduced the amount of reactive oxygen species (ROS) in tissues.
PMCID: PMC4726310  PMID: 26806642
18.  Magnetic bilayer-skyrmions without skyrmion Hall effect 
Nature Communications  2016;7:10293.
Magnetic skyrmions might be used as information carriers in future advanced memories, logic gates and computing devices. However, there exists an obstacle known as the skyrmion Hall effect (SkHE), that is, the skyrmion trajectories bend away from the driving current direction due to the Magnus force. Consequently, the skyrmions in constricted geometries may be destroyed by touching the sample edges. Here we theoretically propose that the SkHE can be suppressed in the antiferromagnetically exchange-coupled bilayer system, since the Magnus forces in the top and bottom layers are exactly cancelled. We show that such a pair of SkHE-free magnetic skyrmions can be nucleated and be driven by the current-induced torque. Our proposal provides a promising means to move magnetic skyrmions in a perfectly straight trajectory in ultra-dense devices with ultra-fast processing speed.
Magnetic skyrmions propagating under an applied current along a nanowire experience the magnus force, deflecting them towards the edges where they may be destroyed, potentially hindering their applications. Here, the authors propose a method to surpass this issue utilizing magnetic bilayers systems.
PMCID: PMC4735649  PMID: 26782905
19.  Rapamycin Inhibits Oxidized Low Density Lipoprotein Uptake in Human Umbilical Vein Endothelial Cells via mTOR/NF-κB/LOX-1 Pathway 
PLoS ONE  2016;11(1):e0146777.
Lectin-like oxidized low-density lipoprotein-1 (LOX-1) is the major receptor for oxidized low density lipoprotein (ox-LDL) uptake in human umbilical vein endothelial cells (HUVECs). Previously, we found that rapamycin inhibited ox-LDL accumulation in HUVECs, and this effect was related to its role in increasing the activity of autophagy-lysosome pathway. In this study, we determined whether rapamycin could also reduce ox-LDL uptake in HUVECs and investigated the underlying signaling mechanisms.
Flow cytometry and live cell imaging showed that rapamycin reduced Dil-ox-LDL accumulation in HUVECs. Furthermore, rapamycin reduced the ox-LDL-induced increase in LOX-1 mRNA and protein levels. Western blotting showed that rapamycin inhibited mechanistic target of rapamycin (mTOR), p70s6k and IκBα phosphorylation triggered by ox-LDL. Flow cytometry implied that mTOR, NF-κB knockdown and NF-κB inhibitors significantly reduced Dil-ox-LDL uptake. Moreover, immunofluorescent staining showed that rapamycin reduced the accumulation of p65 in the nucleus after ox-LDL treatment for 30 h. mTOR knockdown decreased LOX-1 protein production and IκBα phosphorylation induced by ox-LDL. NF-κB knockdown and NF-κB inhibitors reduced LOX-1 protein production, but did not inhibit mTOR phosphorylation stimulated by ox-LDL.
These findings demonstrate that rapamycin reduce mTOR phosphorylation and subsequently inhibit NF-κB activation and suppresses LOX-1, resulting in a reduction in ox-LDL uptake in HUVECs.
PMCID: PMC4709184  PMID: 26752047
20.  Probing the molecular design of hyper-branched aryl polyesters towards lubricant applications 
Scientific Reports  2016;6:18624.
We report novel polymeric materials that may be used as viscosity index improvers (VII) for lubricant applications. Our efforts included probing the comb-burst hyper-branched aryl polyester architecture for beneficial viscosity and friction behavior when utilized as an additive in a group I oil. The monomer was designed as to undergo polymerization via polycondensation within the architectural construct (AB2), typical of hyperbranched polymers. The monomer design was comprised of aliphatic arms (12 or 16 methylenes) to provide the necessary lipophilicity to achieve solubility in a non-polar medium. Once polymerized, via catalyst and heat, the surface alcohols were functionalized with fatty acids (lauric and palmitic). Controlling the aliphatic nature of the internal arms and peripheral end-groups provided four unique flexible polymer designs. Changing the reaction time and concentration provided opportunities to investigate the influence of molecular weight and branching density on oil-solubility, viscosity, and friction. Oil-solubility was found to decrease with fewer internal carbons, but the number of internal carbons appears to have little influence on the bulk solution viscosity. At concentrations of 2 wt % in a group I base oil, these polymer additives demonstrated an improved viscosity index and reduced friction coefficient, validating the basic approach.
PMCID: PMC4700471  PMID: 26727881
22.  Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial 
The 2014 west African Zaire Ebola virus epidemic prompted worldwide partners to accelerate clinical development of replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein (ChAd3-EBO-Z). We aimed to investigate the safety, tolerability, and immunogenicity of ChAd3-EBO-Z in Malian and US adults, and assess the effect of boosting of Malians with modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo).
In the phase 1, single-blind, randomised trial of ChAd3-EBO-Z in the USA, we recruited adults aged 18–65 years from the University of Maryland medical community and the Baltimore community. In the phase 1b, open-label and double-blind, dose-escalation trial of ChAd3-EBO-Z in Mali, we recruited adults 18–50 years of age from six hospitals and health centres in Bamako (Mali), some of whom were also eligible for a nested, randomised, double-blind, placebo-controlled trial of MVA-BN-Filo. For randomised segments of the Malian trial and for the US trial, we randomly allocated participants (1:1; block size of six [Malian] or four [US]; ARB produced computer-generated randomisation lists; clinical staff did randomisation) to different single doses of intramuscular immunisation with ChAd3-EBO-Z: Malians received 1 × 1010 viral particle units (pu), 2·5 × 1010 pu, 5 × 1010 pu, or 1 × 1011 pu; US participants received 1 × 1010 pu or 1 × 1011 pu. We randomly allocated Malians in the nested trial (1:1) to receive a single dose of 2 × 108 plaque-forming units of MVA-BN-Filo or saline placebo. In the double-blind segments of the Malian trial, investigators, clinical staff, participants, and immunology laboratory staff were masked, but the study pharmacist (MK), vaccine administrator, and study statistician (ARB) were unmasked. In the US trial, investigators were not masked, but participants were. Analyses were per protocol. The primary outcome was safety, measured with occurrence of adverse events for 7 days after vaccination. Both trials are registered with, numbers NCT02231866 (US) and NCT02267109 (Malian).
Between Oct 8, 2014, and Feb 16, 2015, we randomly allocated 91 participants in Mali (ten [11%] to 1 × 1010 pu, 35 [38%] to 2·5 × 1010 pu, 35 [38%] to 5 × 1010 pu, and 11 [12%] to 1 × 1011 pu) and 20 in the USA (ten [50%] to 1 × 1010 pu and ten [50%] to 1 × 1011 pu), and boosted 52 Malians with MVA-BN-Filo (27 [52%]) or saline (25 [48%]). We identified no safety concerns with either vaccine: seven (8%) of 91 participants in Mali (five [5%] received 5 × 1010 and two [2%] received 1 × 1011 pu) and four (20%) of 20 in the USA (all received 1 × 1011 pu) given ChAd3-EBO-Z had fever lasting for less than 24 h, and 15 (56%) of 27 Malians boosted with MVA-BN-Filo had injection-site pain or tenderness.
1 × 1011 pu single-dose ChAd3-EBO-Z could suffice for phase 3 efficacy trials of ring-vaccination containment needing short-term, high-level protection to interrupt transmission. MVA-BN-Filo boosting, although a complex regimen, could confer long-lived protection if needed (eg, for health-care workers).
Wellcome Trust, Medical Research Council UK, Department for International Development UK, National Cancer Institute, Frederick National Laboratory for Cancer Research, Federal Funds from National Institute of Allergy and Infectious Diseases.
PMCID: PMC4700389  PMID: 26546548
23.  Crystal structure of a mixed-ligand terbium(III) coordination polymer containing oxalate and formate ligands, having a three-dimensional fcu topology 
The crystal structure of catena-[(μ 3-formato)(μ 4-oxalato)terbium(III)] features a three-dimensional 12-connected fcu topology with point symbol (324.436.56), exhibiting thermal stability up to 623 K and strong green photoluminescence in the solid state at room temperature.
The title compound, poly[(μ 3-formato)(μ 4-oxalato)terbium(III)], [Tb(CHO2)(C2O4)]n, is a three-dimensional coordination polymer, and is isotypic with the LaIII, CeIII and SmIII analogues. The asymmetric unit contains one TbIII ion, one formate anion (CHO2 −) and half of an oxalate anion (C2O4 2−), the latter being completed by application of inversion symmetry. The TbIII ion is nine-coordinated in a distorted tricapped trigonal–prismatic manner by two chelating carboxyl­ate groups from two C2O4 2− ligands, two carboxyl­ate oxygen atoms from another two C2O4 2− ligands and three oxygen atoms from three CHO2 − ligands, with the Tb—O bond lengths and the O—Tb—O bond angles ranging from 2.4165 (19) to 2.478 (3) Å and 64.53 (6) to 144.49 (4)°, respectively. The CHO2 − and C2O4 2− anions adopt μ 3-bridging and μ 4-chelating-bridging coordination modes, respectively, linking adjacent TbIII ions into a three-dimensional 12-connected fcu topology with point symbol (324.436.56). The title compound exhibits thermal stability up to 623 K, and also displays strong green photoluminescence in the solid state at room temperature.
PMCID: PMC4704756  PMID: 26870593
coordination polymers; crystal structure; lanthanide; luminescence; terbium(III)
24.  Intravenous high mobility group box 1 upregulates the expression of HIF-1α in the myocardium via a protein kinase B-dependent pathway in rats following acute myocardial ischemia 
Molecular Medicine Reports  2015;13(2):1211-1219.
The effects of intravenous high mobility group box 1 (HMGB1) on myocardial ischemia/reperfusion (I/R) injury remains to be elucidated. The purpose of the present study was to investigate the effects of intravenous HMGB1 on the expression of hypoxia inducible factor-1α (HIF-1α) in the myocardium of rats following acute myocardial ischemia, and to examine the effects of intravenous HMGB1 on myocardial I/R injury. Male Wistar rats were divided into the following groups: Sham operation group (n=10), a group exposed to ischemia for 30 min and reperfusion for 4 h (I/R group) as a control (n=10), an HMGB group, in which 100 ng/kg HMGB was administered intravenously 30 min prior to ischemia (n=10), an LY group, in whic LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), was administered intravenously (0.3 mg/kg) 40 min prior to ischemia (n=10), and the HMGB1+LY group, in which HMGB1 (100 ng/kg) and LY294002 (0.3 mg/kg) were administered intravenously 30 min and 40 min prior to ischemia, respectively (n=10). The serum levels of cardiac troponin I (cTnI) and tumor necrosis factor-α (TNF-α), and myocardial infarct size were measured. The expression levels of phosphorylated Akt and HIF-1α were investigated using western blot analyses. The results showed that pre-treatment with HMGB1 significantly decreased serum levels of cTnI, and TNF-α, and reduced myocardial infarct size following 4 h reperfusion (all P<0.05). HMGB1 also increased the expression levels of HIF-1α and p-Akt induced by I/R (P<0.05). LY294002 was found to eliminate the effects of intravenous HMGB1 on myocardial I/R injury (P<0.05). These results suggest that intravenous pre-treatment with HMGB1 may exert its cardioprotective effects via the upregulation of the myocardial expression of HIF-1α, which may be regulated by the PI3K/Akt signaling pathway, in rats following acute myocardial I/R.
PMCID: PMC4732844  PMID: 26648172
high mobility group box 1; acute myocardial ischemia; ischemia reperfusion injury; hypoxia inducible factor-1α; rats
25.  A Synthetic Lethality Screen Using a Focused siRNA Library to Identify Sensitizers to Dasatinib Therapy for the Treatment of Epithelial Ovarian Cancer 
PLoS ONE  2015;10(12):e0144126.
Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC). The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK) and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to have minimal activity. We hypothesized that synthetic lethality screens performed using a cogently designed siRNA library would identify second-site molecular targets that could synergize with SFK inhibition and improve dasatinib efficacy. Using a systematic approach, we performed primary siRNA screening using a library focused on 638 genes corresponding to a network centered on EGFR, HER2, and the SFK-scaffolding proteins BCAR1, NEDD9, and EFS to screen EOC cells in combination with dasatinib. We followed up with validation studies including deconvolution screening, quantitative PCR to confirm effective gene silencing, correlation of gene expression with dasatinib sensitivity, and assessment of the clinical relevance of hits using TCGA ovarian cancer data. A refined list of five candidates (CSNK2A1, DAG1, GRB2, PRKCE, and VAV1) was identified as showing the greatest potential for improving sensitivity to dasatinib in EOC. Of these, CSNK2A1, which codes for the catalytic alpha subunit of protein kinase CK2, was selected for additional evaluation. Synergistic activity of the clinically relevant inhibitor of CK2, CX-4945, with dasatinib in reducing cell proliferation and increasing apoptosis was observed across multiple EOC cell lines. This overall approach to improving drug efficacy can be applied to other targeted agents that have similarly shown poor clinical activity.
PMCID: PMC4670180  PMID: 26637171

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